Positive and negative regulators of the metallothionein gene (Review)

  • Authors:
    • Shinichiro Takahashi
  • View Affiliations

  • Published online on: March 9, 2015     https://doi.org/10.3892/mmr.2015.3459
  • Pages: 795-799
Metrics: Total Views: 0 (Spandidos Publications: | PMC Statistics: )
Total PDF Downloads: 0 (Spandidos Publications: | PMC Statistics: )


Abstract

Metallothioneins (MTs) are metal‑binding proteins involved in diverse processes, including metal homeostasis and detoxification, the oxidative stress response and cell proliferation. Aberrant expression and silencing of these genes are important in a number of diseases. Several positive regulators of MT genes, including metal‑responsive element‑binding transcription factor (MTF)‑1 and upstream stimulatory factor (USF)‑1, have been identified and mechanisms of induction have been well described. However, the negative regulators of MT genes remain to be elucidated. Previous studies from the group of the present review have revealed that the hematopoietic master transcription factor, PU.1, directly represses the expression levels of MT genes through its epigenetic activities, and upregulation of MT results in the potent inhibition of myeloid differentiation. The present review focuses on PU.1 and several other negative regulators of this gene, including PZ120, DNA methyltransferase 3a with Mbd3 and Brg1 complex, CCAAT enhancer binding protein α and Ku protein, and describes the suppression of the MT genes through these transcription factors.

1. Introduction

The metallothioneins (MTs) are a group of low molecular weight, cysteine-rich intracellular proteins, which are involved in maintaining intracellular metal homeostasis by binding metals, including zinc and copper. There are 10 functional isoforms of MTs, which are divided into four classes, designated MT-1 to -4, on the basis of small differences in protein sequence, expression and characteristics (1,2). They maintain transition metal ion homeostasis and redox balance, serve as anti-oxidants and protect against DNA damage and apop-tosis (3). Reduced expression of MT has been observed in liver (4), colon (5) and prostate (6) cancer. It was suggested that during the transformation of normal colorectal tissue to adenomatous polyps and adenocarcinoma, a progressive decrease in the expression of MT occurs (7,8). The role of MT in these types of cancer remains to be elucidated, however, considering its anti-oxidant activity and its protective potential against DNA damage, this reduction may increase susceptibility to toxin-induced damage. Indeed, an MT knockout in mice has been reported to induce a higher rate of induced carcinogenesis (9). Conversely, aberrant overexpression of MT has been observed in various types of human cancer, including breast cancer, gallbladder cancer, melanoma and lymphoma (1013). It has been suggested that the overexpression of MT may protect cells from free radical-induced DNA damage and lipid peroxidation (14). Overexpression of MT has been demonstrated to be important in drug resistance, since nuclear expression of MT protects DNA in ovarian cancer cells from the toxic effect of treatment with cisplatin (15). This indicates that aberrant under/over-expression of MT are important in various types of cancer.

A study revealed that the hematopoietic master transcription factor, PU.1, directly suppresses the MT-1A and MT-1G promoter through DNA methylation and histone deacetylase (HDAC) activity (16). Additionally, it was revealed that MT-1A is suppressed, while the expression of PU.1 is induced, during 12-O-tetradecanoylphorbol-13-acetate (TPA)-induced monocytic differentiation of THP-1 cells (17). Notably, the suppression of MT-1s by PU.1 is required for the proper differentiation of myeloid cells.

Although there are several reviews regarding the regulation of the MT gene (1820), reviews regarding the suppressive regulation of MT genes are relatively scarce. Therefore, this review summarized the regulation of MT genes and particularly focused on PU.1 and other suppressive regulators of the MT genes.

2. Positive regulators of MT genes

The basal activity of MT is regulated by several general transcription factors, including the TFIID complex comprising TATA-binding protein (TBP), TBP associated factors and Sp1 (1820). In addition, MT can be activated by a variety of stimuli, including metal ions, cytokines and growth factors (1). Several inducible expression regulators of the MT genes have been identified, including metal-responsive element (MRE)-binding transcription factor (MTF)-1 (21,22), upstream stimulatory factor (USF)-1 (23) and nuclear factor (NF)1 (24). Since a number of reviews summarize the details of the positive regulation of MT genes (1820), the present review describes the above essential factors.

The MTF-1 gene is a central regulator of the metal-inducible expression levels of MT-1 and MT-2. In addition to zinc, other heavy metals (e.g. cadmium), hypoxia, oxidative stress, stress hormones (glucocorticoids), nitric oxide and high temperature induce the transcriptional activity of MTF-1 (2528). Andrews et al (23) reported that MTF-1 is essential for the upregulation of the gene expression of MT-1 in visceral endoderm cells and that optimal expression is dependent upon the interactions of the basic helix-loop-helix transcription factor, USF -1, with an E-box-1 containing sequence at −223 bp in the MT-1 promoter (23).

NF1 is a protein expressed ubiquitously in higher eukaryotes, and distinct highly conserved genes encode four isoforms of the NF1 protein (NF1-A, NF1-B, NF1-C and NF1-X) (2931). NF1 binding sites were identified in various MT promoters, with the exception of MT-IB (19). LaRochelle et al (24) previously demonstrated that NF1 binds to the mouse MT-1 promoter in vivo and this binding is zinc inducible and MTF-1 dependent. It was revealed by transient transfection assays into HepG2 cells, that NF1 activates the mouse MT-1 promoter. The authors demonstrated that NF1 and MTF-1 synergistically activate the mouse MT-1 gene in response to metal ions (24). However, Majumder et al (32,33) previously demonstrated that NF1 isoforms inhibit the activity of the MT-1 promoter in HepG2 cells. This is contradictory to the earlier study (24), however, this result may be due to the experimental condition in which Majumder et al have used extremely high expression levels of the NF1 vector, ~30- to 1000-fold more vector compared with the earlier study (24). LaRochelle et al demonstrated that the expression levels of the transcriptionally active mutant of NF1 reduced the zinc-induced MT-1 promoter by up to 50%, in a dose-dependent manner and may also indicate that NF1 is a positive regulator of the gene expression of MT-1 (24).

3. Negative regulators of MT genes

To date, several factors are reported to regulate the suppression of MT genes, including PZ120 (34), DNA methyltransferase (Dnmt) 3a with Mbd3 and Brg1 complex (35), C/EBP α (36), Ku protein (37) and PU.1 (16,17).

Tang et al (34), reported the cloning of a novel zinc finger protein with a molecular mass of 120 kDa (PZ120), through Southwestern cloning, which interacts specifically with the human gene transcription initiation site of MT-2A. PZ120 is a ubiquitously expressed protein and possesses a conserved poxvirus and zinc finger (POZ) motif, which is a structure existing in several transcriptional repressors. This protein has been revealed to repress the transcription of the MT-2A promoter (34).

Datta et al (35) purified DNA methyltransferase (Dnmt) 3a from mouse lymphosarcoma cells and revealed that Dnmt 3a-associated polypeptides identified the methyl CpG binding protein, Mbd3, histone deacetylase 1 and components of the Brg1 complex (35). A chromatin immunoprecipitation assay reveled that Dnmt 3a, Mbd3 and Brg1 are associated with a transcriptionally silent methylated MT-1 promoter in the mouse lymphosarcoma cells. The authors further clarified that the catalytic activity of Dnmt3a was not important for the repression of the MT-1 gene; however, ATP-dependent chromatin remodeling of Brg1 was (35). It was also revealed that methylated and unmethylated MT-1 promoters are differentially regulated by several methyl CpG binding proteins, including methyl CpG binding protein (MeCP) 2 and Mbd1, 2 and 4 (38).

CCAAT enhancer binding protein (C/EBP) is important in the terminal differentiation of cells, particularly in myeloid cells and adipose cells (39). Yin et al (36) demonstrated that forced expression of C/EBPα decreased the expression levels of the MT isoforms 1A, B, F and H, and 2A and 3 in prostate cancer cells, and that this suppression is mediated through its promoter activity. Furthermore, it was revealed that the forced expression of C/EBPα led to an increased cytotoxicity of zinc in prostate cancer cells (36). However, in human hepatocellular carcinoma cells, the inactivation of C/EBPα through the activation of phosphatidylinositol 3-kinase led to the downregulation of the expression of MT (4). Therefore, the role of C/EBPα in the gene regulation of MT may differ among tissues.

It was previously reported that the large subunit (p80) of the Ku protein contained repressor activity for the MT-1 promoter (37). Additionally, it was revealed that this repression is due to the hypermethylation of a CpG island in the MT-1 promoter (40).

Rodent and human MT genes contain CpG islands in their promoter (19,41). It was first reported in 1981 that DNA methylation controls the inducibility of the mouse MT-1 gene (42). Since then, >100 studies have been published demonstrating that the MT promoter is regulated by DNA methylation in its promoter region. Arriaga et al (43) demonstrated from the analysis of colorectal cancer, that the mRNA expression levels of five isoforms (MT-1G, 1E, 1F, 1H and 1M) were lost during the transition from normal mucosa to tumor, whereas MT-1X and MT-2 were less downregulated and their expression was correlated with overall protein positivity. It was also demonstrated that hypermethylation of the MT-1G gene occurred in cell lines and in 29% of tumor samples. Faller et al (44) analyzed specimens from patients with melanoma and demonstrated that in 1/17 (6%) of the benign naevi, 16/43 (37%) primary tumors and 6/13 (46%) of metastases exhibited MT-1E gene methylation. Peng et al (45) revealed using quantitative pyrosequencing, unique DNA methylation profiles in the MT-3 promoter region in esophageal adenocarcinomas (EACs). This previous study concluded that EACs are characterized by frequent epigenetic silencing of the MT-3 gene. In addition, in colon cancer, not only DNA methylation (41,43), but the loss of heterozygosity (5) is also important in the downregulation of the MT genes (MT-1F, MT-1G, MT-1X and MT-2A).

4. PU.1-a master hematopoietic transcription factor previously identified as a novel negative regulator of MT-1s

A previous study revealed that MT-1s genes are epigenetically suppressed by the activity of PU.1 (16). PU.1 is a hematopoietic master transcription factor, predominantly expressed in immature myeloid cells and B cells, and downregulation of this factor is important in various hematological malignancies (46,47). To identify downstream target genes of PU.1, the authors generated cell lines expressing reduced levels of PU.1 by stable transfection of PU.1 short inhibitory RNAs into K562 human myeloid leukemia cells (K562PU.1KD cells) and PU.1-overexpressing K562 cells (K562PU.1OE cells). Dual microarray analyses were performed using these cell lines. Notably, the expression levels of all the functional MT isoforms expressed in humans (MT-1A, -B, -E, -F, -G, -H and -X and MT-2) were increased by varying degrees in the K562PU.1KD cells. Furthermore, there were negative correlations between the mRNA expression of PU.1 and the mRNA expression of the MT-1s in 43 primary specimens from patients with acute myeloid leukemia (AML). Additionally, it was revealed that PU.1 directly binds and epigenetically suppresses the MT-1s promoter, in concert with MeCP2, through the suppression of the enzymatic activities of HDAC and Dnmt. The proportion of the methylated CpG sites is tightly associated with the expression levels in MT-1s promoters (16). Next, the authors examined whether the expression levels of PU.1 and MT-1A are indeed correlated with each other, and whether the expression of MT-1A is regulated by PU.1 during TPA-induced THP-1 monocyte differentiation. As a result, it was revealed that the expression of MT-1s is suppressed during monocytic differentiation in the THP-1 cells (17). Chromatin immunoprecipitation analysis demonstrated that PU.1 and MeCP2 bind to the same region in the MT-1A promoter, and the binding of these proteins to this promoter was increased during differentiation. Consistently, the proportion of methylated CpG sites was markedly increased during differentiation (17). These results suggest that MT-1s are repressed through the epigenetic activity of PU.1 in hematopoietic cells.

5. Conclusion

The positive and negative regulators described in this review are summarized in Fig. 1. The consequences of these MT gene regulations have been reported to be through the normal physiological aspects to disease, including inflammation, aging and malignancies (1,3,48,49). It was recently demonstrated that the overexpression of MT-1G potently inhibited the retinoic acid induced myeloid differentiation of NB4 acute promyelocytic leukemia cells (50). This is consistent with the literature, suggesting that the downregulation of PU.1 is the cause of AML (46) and results in the overexpression of MT, leading to the inhibition of differentiation, which is important in leukemogenesis.

MTs are multifunctional proteins and exhibit different biological behavior in different tissues. Therefore, further clarifying the underlying mechanisms and the roles of MT, may lead to an improved understanding of the biology of normal physiology and malignancies from another aspects.

Acknowledgments

The author would like to thank everyone who helped the research during this decade, regarding the analysis of the PU.1 transcription factor, and the regulation and functions of the MT gene. This study was supported in part by Grants-in-Aid for Scientific Research (grant no. 26460685) from the Ministry of Education, Culture, Sports, Science and Technology, Japan, the Takeda Science Foundation, and a foundation from Kitasato University School of Allied Health Sciences (Grant-in-Aid for Research Project, grant no. 2014-1003).

References

1 

Takahashi S: Molecular functions of metallothionein and its role in hematological malignancies. J Hematol Oncol. 5:412012. View Article : Google Scholar : PubMed/NCBI

2 

Hamer DH: Metallothionein. Annu Rev Biochem. 55:913–951. 1986. View Article : Google Scholar : PubMed/NCBI

3 

Cherian MG, Jayasurya A and Bay BH: Metallothioneins in human tumors and potential roles in carcinogenesis. Mutat Res. 533:201–209. 2003. View Article : Google Scholar : PubMed/NCBI

4 

Datta J, Majumder S, Kutay H, et al: Metallothionein expression is suppressed in primary human hepatocellular carcinomas and is mediated through inactivation of CCAAT/enhancer binding protein alpha by phosphatidylinositol 3-kinase signaling cascade. Cancer Res. 67:2736–2746. 2007. View Article : Google Scholar : PubMed/NCBI

5 

Yan DW, Fan JW, Yu ZH, et al: Downregulation of metallothionein 1F, a putative oncosuppressor, by loss of heterozygosity in colon cancer tissue. Biochim Biophys Acta. 1822:918–926. 2012. View Article : Google Scholar : PubMed/NCBI

6 

Wei H, Desouki MM, Lin S, Xiao D, Franklin RB and Feng P: Differential expression of metallothioneins (MTs) 1, 2, and 3 in response to zinc treatment in human prostate normal and malignant cells and tissues. Mol Cancer. 7:72008. View Article : Google Scholar : PubMed/NCBI

7 

Theocharis SE, Margeli AP, Klijanienko JT and Kouraklis GP: Metallothionein expression in human neoplasia. Histopathology. 45:103–118. 2004. View Article : Google Scholar : PubMed/NCBI

8 

Ofner D, Maier H, Riedmann B, et al: Immunohistochemical metallothionein expression in colorectal adenocarcinoma: correlation with tumour stage and patient survival. Virchows Arch. 425:491–497. 1994. View Article : Google Scholar : PubMed/NCBI

9 

Zhang B, Satoh M, Nishimura N, et al: Metallothionein deficiency promotes mouse skin carcinogenesis induced by 7,12-dimethylbenz[a]anthracene. Cancer Res. 58:4044–4046. 1998.PubMed/NCBI

10 

Poulsen CB, Borup R, Borregaard N, Nielsen FC, Møller MB and Ralfkiaer E: Prognostic significance of metallothionein in B-cell lymphomas. Blood. 108:3514–3519. 2006. View Article : Google Scholar : PubMed/NCBI

11 

Bay BH, Jin R, Huang J and Tan PH: Metallothionein as a prognostic biomarker in breast cancer. Exp Biol Med (Maywood). 231:1516–1521. 2006.

12 

Shukla VK, Aryya NC, Pitale A, et al: Metallothionein expression in carcinoma of the gallbladder. Histopathology. 33:154–157. 1998. View Article : Google Scholar : PubMed/NCBI

13 

Weinlich G, Eisendle K, Hassler E, Baltaci M, Fritsch PO and Zelger B: Metallothionein-overexpression as a highly significant prognostic factor in melanoma: a prospective study on 1270 patients. Br J Cancer. 94:835–841. 2006. View Article : Google Scholar : PubMed/NCBI

14 

You HJ, Lee KJ and Jeong HG: Overexpression of human metallothionein-III prevents hydrogen peroxide-induced oxidative stress in human fibroblasts. FEBS Lett. 521:175–179. 2002. View Article : Google Scholar : PubMed/NCBI

15 

Surowiak P, Materna V, Maciejczyk A, et al: Nuclear metallothionein expression correlates with cisplatin resistance of ovarian cancer cells and poor clinical outcome. Virchows Arch. 450:279–285. 2007. View Article : Google Scholar : PubMed/NCBI

16 

Imoto A, Okada M, Okazaki T, Kitasato H, Harigae H and Takahashi S: Metallothionein-1 isoforms and vimentin are direct PU.1 downstream target genes in leukemia cells. J Biol Chem. 285:10300–10309. 2010. View Article : Google Scholar : PubMed/NCBI

17 

Suzuki S, Nakano H and Takahashi S: Epigenetic regulation of the metallothionein-1A promoter by PU.1 during differentiation of THP-1 cells. Biochem Biophys Res Commun. 433:349–353. 2013. View Article : Google Scholar : PubMed/NCBI

18 

Ghoshal K and Jacob ST: Regulation of metallothionein gene expression. Prog Nucleic Acid Res Mol Biol. 66:357–384. 2001.

19 

Laukens D, Waeytens A, De Bleser P, Cuvelier C and De Vos M: Human metallothionein expression under normal and pathological conditions: mechanisms of gene regulation based on in silico promoter analysis. Crit Rev Eukaryot Gene Expr. 19:301–317. 2009. View Article : Google Scholar : PubMed/NCBI

20 

Haq F, Mahoney M and Koropatnick J: Signaling events for metallothionein induction. Mutat Res. 533:211–226. 2003. View Article : Google Scholar : PubMed/NCBI

21 

Radtke F, Heuchel R, Georgiev O, et al: Cloned transcription factor MTF-1 activates the mouse metallothionein I promoter. EMBO J. 12:1355–1362. 1993.PubMed/NCBI

22 

Palmiter RD: Regulation of metallothionein genes by heavy metals appears to be mediated by a zinc-sensitive inhibitor that interacts with a constitutively active transcription factor, MTF-1. Proc Natl Acad Sci USA. 91:1219–1223. 1994. View Article : Google Scholar : PubMed/NCBI

23 

Andrews GK, Lee DK, Ravindra R, et al: The transcription factors MTF-1 and USF1 cooperate to regulate mouse metallothionein-I expression in response to the essential metal zinc in visceral endoderm cells during early development. EMBO J. 20:1114–1122. 2001. View Article : Google Scholar : PubMed/NCBI

24 

LaRochelle O, Labbe S, Harrisson JF, et al: Nuclear factor-1 and metal transcription factor-1 synergistically activate the mouse metallothionein-1 gene in response to metal ions. J Biol Chem. 283:8190–8201. 2008. View Article : Google Scholar : PubMed/NCBI

25 

Westin G and Schaffner W: A zinc-responsive factor interacts with a metal-regulated enhancer element (MRE) of the mouse metallothionein-I gene. EMBO J. 7:3763–3770. 1988.PubMed/NCBI

26 

Dalton T, Palmiter RD and Andrews GK: Transcriptional induction of the mouse metallothionein-I gene in hydrogen peroxide-treated Hepa cells involves a composite major late transcription factor/antioxidant response element and metal response promoter elements. Nucleic Acids Res. 22:5016–5023. 1994. View Article : Google Scholar : PubMed/NCBI

27 

Murphy BJ, Andrews GK, Bittel D, et al: Activation of metallothionein gene expression by hypoxia involves metal response elements and metal transcription factor-1. Cancer Res. 59:1315–1322. 1999.PubMed/NCBI

28 

Günther V, Lindert U and Schaffner W: The taste of heavy metals: gene regulation by MTF-1. Biochim Biophys Acta. 1823:1416–1425. 2012. View Article : Google Scholar : PubMed/NCBI

29 

Paonessa G, Gounari F, Frank R and Cortese R: Purification of a NF1-like DNA-binding protein from rat liver and cloning of the corresponding cDNA. EMBO J. 7:3115–3123. 1988.PubMed/NCBI

30 

Rupp RA, Kruse U, Multhaup G, Göbel U, Beyreuther K and Sippel AE: Chicken NFI/TGGCA proteins are encoded by at least three independent genes: NFI-A, NFI-B and NFI-C with homologues in mammalian genomes. Nucleic Acids Res. 18:2607–2616. 1990. View Article : Google Scholar : PubMed/NCBI

31 

Meisterernst M, Rogge L, Foeckler R, Karaghiosoff M and Winnacker EL: Structural and functional organization of a porcine gene coding for nuclear factor I. Biochemistry. 28:8191–8200. 1989. View Article : Google Scholar : PubMed/NCBI

32 

Majumder S, Ghoshal K, Gronostajski RM and Jacob ST: Downregulation of constitutive and heavy metal-induced metallothionein-I expression by nuclear factor I. Gene Expr. 9:203–215. 2001.PubMed/NCBI

33 

Jacob ST, Majumder S and Ghoshal K: Suppression of metallothionein-I/II expression and its probable molecular mechanisms. Environ Health Perspect. 110(Suppl 5): 827–830. 2002. View Article : Google Scholar : PubMed/NCBI

34 

Tang CM, Westling J and Seto E: trans repression of the human metallothionein IIA gene promoter by PZ120, a novel 120-kilo-dalton zinc finger protein. Mol Cell Biol. 19:680–689. 1999.

35 

Datta J, Majumder S, Bai S, et al: Physical and functional interaction of DNA methyltransferase 3A with Mbd3 and Brg1 in mouse lymphosarcoma cells. Cancer Res. 65:10891–10900. 2005. View Article : Google Scholar : PubMed/NCBI

36 

Yin H, Smith M and Glass J: Stable expression of C/EBPalpha in prostate cancer cells down-regulates metallothionein and increases zinc-induced toxicity. Prostate. 62:209–216. 2005. View Article : Google Scholar

37 

Ghoshal K, Li Z and Jacob ST: Overexpression of the large subunit of the protein Ku suppresses metallothionein-I induction by heavy metals. Proc Natl Acad Sci USA. 95:10390–10395. 1998. View Article : Google Scholar : PubMed/NCBI

38 

Majumder S, Kutay H, Datta J, Summers D, Jacob ST and Ghoshal K: Epigenetic regulation of metallothionein-i gene expression: differential regulation of methylated and unmethylated promoters by DNA methyltransferases and methyl CpG binding proteins. J Cell Biochem. 97:1300–1316. 2006. View Article : Google Scholar

39 

Koschmieder S, Halmos B, Levantini E and Tenen DG: Dysregulation of the C/EBPalpha differentiation pathway in human cancer. J Clin Oncol. 27:619–628. 2009. View Article : Google Scholar :

40 

Majumder S, Ghoshal K, Li Z and Jacob ST: Hypermethylation of metallothionein-I promoter and suppression of its induction in cell lines overexpressing the large subunit of Ku protein. J Biol Chem. 274:28584–28589. 1999. View Article : Google Scholar : PubMed/NCBI

41 

Mao J, Yu H, Wang C, et al: Metallothionein MT1M is a tumor suppressor of human hepatocellular carcinomas. Carcinogenesis. 33:2568–2577. 2012. View Article : Google Scholar : PubMed/NCBI

42 

Compere SJ and Palmiter RD: DNA methylation controls the inducibility of the mouse metallothionein-I gene lymphoid cells. Cell. 25:233–240. 1981. View Article : Google Scholar : PubMed/NCBI

43 

Arriaga JM, Levy EM, Bravo AI, et al: Metallothionein expression in colorectal cancer: relevance of different isoforms for tumor progression and patient survival. Hum Pathol. 43:197–208. 2012. View Article : Google Scholar

44 

Faller WJ, Rafferty M, Hegarty S, et al: Metallothionein 1E is methylated in malignant melanoma and increases sensitivity to cisplatin-induced apoptosis. Melanoma Res. 20:392–400. 2010.PubMed/NCBI

45 

Peng D, Hu TL, Jiang A, et al: Location-specific epigenetic regulation of the metallothionein 3 gene in esophageal adenocarcinomas. PLoS One. 6:e220092011. View Article : Google Scholar : PubMed/NCBI

46 

Rosenbauer F, Wagner K, Kutok JL, et al: Acute myeloid leukemia induced by graded reduction of a lineage-specific transcription factor, PU.1. Nat Genet. 36:624–630, Epub 2004 May 2016. 2004. View Article : Google Scholar : PubMed/NCBI

47 

Pettersson M, Sundström C, Nilsson K and Larsson LG: The hematopoietic transcription factor PU.1 is downregulated in human multiple myeloma cell lines. Blood. 86:2747–2753. 1995.PubMed/NCBI

48 

Inoue K and Takano H: Metallothionein as a negative regulator of pulmonary inflammation. Curr Pharm Biotechnol. 14:414–419. 2013. View Article : Google Scholar : PubMed/NCBI

49 

Mocchegiani E, Costarelli L, Basso A, Giacconi R, Piacenza F and Malavolta M: Metallothioneins, ageing and cellular senescence: a future therapeutic target. Curr Pharm Des. 19:1753–1764. 2013.

50 

Hirako N, Nakano H and Takahashi S: A PU.1 suppressive target gene, metallothionein 1G, inhibits retinoic acid-induced NB4 cell differentiation. PLoS One. 9:e1032822014. View Article : Google Scholar : PubMed/NCBI

Related Articles

Journal Cover

July 2015
Volume 12 Issue 1

Print ISSN: 1791-2997
Online ISSN:1791-3004

Sign up for eToc alerts

Recommend to Library

Copy and paste a formatted citation
APA
Takahashi, S. (2015). Positive and negative regulators of the metallothionein gene (Review). Molecular Medicine Reports, 12, 795-799. https://doi.org/10.3892/mmr.2015.3459
MLA
Takahashi, S."Positive and negative regulators of the metallothionein gene (Review)". Molecular Medicine Reports 12.1 (2015): 795-799.
Chicago
Takahashi, S."Positive and negative regulators of the metallothionein gene (Review)". Molecular Medicine Reports 12, no. 1 (2015): 795-799. https://doi.org/10.3892/mmr.2015.3459